European Journal of Obstetrics & Gynecology and Reproductive Biology 166 (2013) 117123

Contents lists available at SciVerse ScienceDirect

European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Review

Pathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low

platelet count (HELLP): a review
Ulrich Abildgaard a,*, Ketil Heimdal b
a
Department of Haematology, Oslo University Hospital, Oslo, Norway
b
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

A R T I C L E I N F O A B S T R A C T

Article history: HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome is serious for the mother
Received 30 January 2012 and the offspring. HELLP occurs in 0.20.8% of pregnancies and in 7080% of cases it coexists with
Received in revised form 28 August 2012 preeclampsia (PE). This review concerns the pathogenetic mechanisms of HELLP syndrome with an
Accepted 30 September 2012
emphasis on differences between HELLP and early onset PE. The syndromes show a familial tendency. A
previous HELLP pregnancy is associated with an increased risk of HELLP as well as PE in subsequent
Keywords: pregnancies, indicating related etiologies. No single world-wide genetic cause for excessive risk of HELLP
HELLP
or PE has been identied. Combinations of multiple gene variants, each with a moderate risk, with
Preeclampsia
Pathogenesis
contributing effects of maternal and environmental factors, are probable etiological mechanisms.
Microangiopathy Immunological maladaptation is the most probable trigger of the insult to the invading trophoblast. This
Genetic insult occurs early in the rst trimester, as indicated by marker molecules in maternal blood. The levels
Biomarkers of fetal messenger RNAs in maternal blood at gestational weeks 1520 are signicantly more abnormal
Review in HELLP than in PE, suggesting that the insult is more extensive in HELLP. High levels of HLA-DR in
maternal blood in women with HELLP may suggest a similarity to the rejection reaction. In third
trimester placentas, gene derangement is more extensive in HELLP. Anti-angiogenic factors released into
maternal blood induce the maternal syndromes. Maternal blood levels of anti-angiogenic sFlt1 are
similar, but endoglin and Fas Ligand levels are possibly higher in HELLP than in PE. These factors trigger
the vascular endothelium, resulting in an enhanced inammatory response which is stronger in HELLP.
Activated coagulation and complement, with high levels of activated leucocytes, inammatory
cytokines, TNF-a, and active von Willebrand factor, induce thrombotic microangiopathy with platelet
brin thrombi in microvessels. The angiopathy results in consumption of circulating platelets, causes
hemolysis in affected microvessels and reduces portal blood ow in the liver. Placental Fas Ligand
damages hepatocytes, resulting in periportal necrosis. In about one half of women with HELLP, activation
of coagulation factors and platelets precipitates disseminated intravascular coagulation, which in a
minority becomes uncompensated and contributes to life-threatening multiorgan failure.
2012 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

2. Inheritance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
3. Genetic studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
4. Maternal risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
5. Placental pathogenesis of HELLP and PE. . . . . . . . . . . . . . . . . . . ..................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
5.1. Factors that may predict HELLP and PE and may induce the maternal syndromes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
5.2. Differences between mRNA levels in HELLP and PE . . . . ..................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
5.3. Increased sHLA-DR in HELLP . . . . . . . . . . . . . . . . . . . . . . ..................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
5.4. Gene expression and histopathology in placenta . . . . . . ..................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
6. Pathogenetic mechanisms in the mother with HELLP . . . . . . . . ..................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
6.1. The inammatory response . . . . . . . . . . . . . . . . . . . . . . . ..................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

* Corresponding author. Tel.: +47 22143730.

E-mail address: ulricha@ulrik.uio.no (U. Abildgaard).

0301-2115/$ see front matter 2012 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejogrb.2012.09.026
118 U. Abildgaard, K. Heimdal / European Journal of Obstetrics & Gynecology and Reproductive Biology 166 (2013) 117123

6.2. Thrombotic microangiopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

6.3. Microangiopathic hemolytic anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
6.4. Liver and kidney dysfunctions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
6.5. Disseminated intravascular coagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
6.6. Pathogenetic cascades . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

1. Introduction molecular etiologies of HELLP syndrome and PE are unknown. A

review article from 2008 described the contribution of placenta-
In 1982 Weinstein described a unique group of obstetric derived inammatory cytokines to the pathogenesis of HELLP [10].
patients with hemolysis (H), elevated liver enzymes (EL) and a low Recent reviews on the pathogenesis of PE have focused on the
platelet count (LP), and termed this entity the HELLP syndrome [1]. pathogenic role of immune maladaptation, and the predictive role
The majority of the patients had mild hypertension and Weinstein of fetal markers for PE [6,9,11]. These two latter mechanisms are
regarded the syndrome as a special form of severe preeclampsia. probably as important for the pathogenesis of HELLP. The aim of
He mentioned three reports each describing 35 severely affected the present review is to describe and discuss pathogenetic
patients who probably had suffered from HELLP syndrome. The mechanisms demonstrated in HELLP syndrome, focusing on
patients had often been given a non-obstetric diagnosis and differences between HELLP syndrome and early onset PE.
treatment had been withheld or modied [1].
The HELLP syndrome occurs in about 0.20.8% of pregnancies. 2. Inheritance
It is associated with increased risks of adverse complications for
both mother and fetus [1,2]. Hypertension is present in most Sisters and children of a woman who has sustained HELLP have
cases, but signs of preeclampsia (PE) may be subtle or missing increased risks of HELLP [12]. A woman who has sustained HELLP
[1,2]. Early detection and accurate diagnosis are essential for has a high risk of developing HELLP (1424%) and PE (2228%) in
correct management. The maternal symptoms may be vague and subsequent pregnancies [7,13], suggesting related pathogenetic
easily mistaken for a variety of medical or obstetric complications mechanisms. A population study indicated that 35% of the variance
which should be excluded [2,3]. There are two main diagnostic in susceptibility to PE was attributed to maternal inheritance, and
denitions of the HELLP syndrome. The widely used Tennessee 20% to fetal genetic effects with similar contribution of maternal
classication requires the presence of (1) microangiopathic and paternal inheritance [14].
hemolytic anemia with abnormal blood smear, low serum
haptoglobin and elevated LDH levels, (2) elevation of ASAT above 3. Genetic studies
70 IU/L and LD above 600 IU/L (both enzyme levels more than
twice the upper limit of normal values) or bilirubin more than No world-wide genetic cause for excessive risk of PE or HELLP
1.2 mg/dL, and (3) a platelet count below 100  109 L1 [2]. The has been identied. Results from the Dutch genome-wide scan
incomplete syndrome with only two criteria (ELLP) may be were interpreted as indicating that the genetic background for
clinically less severe. The Mississippi Triple-class classication HELLP was different from that of PE [12] but the ndings have
syndrome further classies the disorder according to the nadir of neither been conrmed nor refuted.
the platelet count [4]. The combined effect of multiple gene variants, each with
HELLP is usually associated with PE, which is dened as de novo moderate risks for HELLP and PE, with additional effects of maternal
hypertension in pregnancy (140/90 mmHg after 20 weeks and environmental factors, is a probable etiological mechanism.
gestation), returning to normal postpartum, and properly docu- Gene variants in the FAS gene, the VEGF gene and the coagulation
mented proteinuria (300 mg/day or a spot urine:creatinine ratio factor V Leiden (FVL) mutation are associated with increased risk of
30 mg/mmol) [5]. PE is about ten times more frequent than HELLP compared to healthy women (Table 1) [1517]. Variants in
HELLP. Onset of PE and HELLP prior to 28 weeks gestation accounts the glucocorticoid receptor gene [18] and the Toll-like receptor gene
for about 2030% of the cases and these early onset types are more [19] increased the risk of HELLP signicantly more than the risk of PE
often associated with severe disease [6,7]. The clinical onset of (Table 1). Risk ratios for HELLP were in the range of 2.34.7 (Table 1),
HELLP may be rapid and associated with severe disease [8]. which are risk ratios commonly found in studies of multifactorial
HELLP and PE are preceded by abnormal placentation in the rst conditions. Women with a previous HELLP pregnancy have a
trimester. The maternal signs occur in the second half of the markedly increased risk of developing chronic hypertension [7],
pregnancy and are thought to represent the response to emitted suggesting a common genetic predisposition or a long-term effect of
products from a stressed placenta [9]. The placental lesion is HELLP.
probably similar in early onset PE and HELLP and is assumed to be Several gene variants are probably associated with a moder-
the major causative factor. In late onset PE, maternal factors may ately increased risk of PE. The association between gene variants
dominate [6]. Early onset PE and HELLP often coexist with fetal and PE was signicant for only a minority of the variants studied
growth restriction (FGR). [20,21]. Genome-wide association studies (GWAS) have disclosed
Delivery is at present the only efcient treatment of HELLP susceptibility genes for PE. The results seem compatible with the
syndrome and PE. The use of corticosteroids, beyond a single assumptions that unfavorable genetic variants and interactions
course for fetal lung maturing, in early onset HELLP is of uncertain between genes regulating maternalfetal interactions are involved
clinical value [3]. Following the delivery of the placenta, the in the development of PE [20,21]. The genetic contributions are
maternal symptoms and signs often disappear but a protracted likely complex, involving numerous genetic variants and fetal
course of severe HELLP syndrome is not unusual. maternal genegene interactions. PE in different women might
Better knowledge of the pathogenesis of the HELLP syndrome have different triggers [20]. These assumptions also seem to be
could lead to improved treatment and prevention. The initial relevant for HELLP.
 U. Abildgaard, K. Heimdal / European Journal of Obstetrics & Gynecology and Reproductive Biology 166 (2013) 117123 119

Table 1
Genetic variants associated with an increased risk of HELLP syndrome.

Gene variant HELLP compared to HELLP (n) OR (95% CI), p Effect Reference

Glucocorticoid receptor gene (GCCR), Healthy pregnant 17 2.89 (1.455.74) p = 0.004 Altered immune sensitivity and [18]
Bell SNP polymorphisms Severe PE 2.56 (1.265.23) p = 0.013 glucocorticoid sensitivity
Toll-like receptor 4 gene (TLR4), Healthy pregnant 177 4.7 (2.01.9) Uncontrolled or harmful inammation, [19]
D299G PE 2.3 (1.34.3) Ineffective immunity
T3991
polymorphisms
VEGF gene (VEGFA), Healthy pregnant 16 3.03 (1.516.08) Angiogenesis and vasculogenesis, [16]
C-460T Healthy pregnant 3.67 (1.056.08) arterial muscular relaxation
G+405C
polymorphisms
FAS (TNFRSF6) gene, homozygous Healthy pregnant 81 2.7 (1.25.9) Immune regulation, apoptosis. Liver disease [15]
polymorphism in A-670G
FV Leiden Healthy pregnant 71 4.5 (1.3115.31) Thrombophilia [17]

4. Maternal risk factors
High body mass index (BMI) and metabolic syndrome 6 months
postpartum were associated with PE but hardly for HELLP [22]. The
antiphospholipid-antibody syndrome (APLS) may be associated
with early onset of HELLP [23]. A rst pregnancy is probably not
associated with a greater risk of HELLP [24] but is associated with a
considerably higher risk of PE [11]. Infertility treatment increases
the risk of PE whereas pre-conceptual exposure to seminal uid
reduces the risk, supporting a pathogenetic role of immune
maladaptation [9]. It is probable, but unknown if these conditions
inuence the risk of HELLP.
5. Placental pathogenesis of HELLP and PE
A placental stage in HELLP, similar to the placental pathology of
PE, has long been recognized [25]. A central issue is whether
maternal immune responses to the invading trophoblasts generate
normal or abnormal placentation [26]. The early development of
the dysfunctional placenta in PE has recently been reviewed [6,9].
Only aspects particularly relevant to HELLP will be mentioned
below.
5.1. Factors that may predict HELLP and PE and may induce the
maternal syndromes
The syncytiotrophoblast membrane which separates maternal
and fetal blood has an abnormal morphology of its brush border in
PE [27,28] and in HELLP [28]. The incorporation of placental
protein 13 (PP 13) in the membrane was abnormal in both
syndromes [28]. High PP 13 concentrations in maternal blood in
the third trimester reect shedding of PP 13 from the aponecrotic
brush border of the membrane [28].
Abnormal concentrations in maternal blood of PP 13 and
angiogenic factors emitted from the placenta have been demon-
strated in HELLP and PE in the rst trimester and onwards [2836].
Alterations in the levels of these early biomarkers are shown in
Table 2. Although changes were similar in HELLP and PE, some
deviations were signicantly greater in HELLP (Table 2). Signi-
cantly reduced PP 13 concentrations in PE already at gestation
weeks 814 in PE and in HELLP [29] indicate that the two placental
syndromes progress early in the rst trimester [37].
In human amnion uid, PP 13 levels were similarly elevated in
PE and HELLP [38]. In cord blood PP 13 levels were low in controls
and in PE, but several-fold higher in HELLP [38]. PP 13 is exclusively
synthesized by syncytiotrophoblast cells [28]. The high PP 13 levels
in cord blood might result from an abnormal syncytiotrophoblast
passage of PP 13 to fetal blood in HELLP, different from PE and
healthy pregnancy. The nding supports the hypothesis of more
profound damage to the syncytiotrophoblast membrane in HELLP.
Increased anti-angiogenic factor levels induce maternal vascu-
lar endothelial dysfunction which causes arterial hypertension and
glomerular endotheliosis in preeclampsia, as recently reviewed
[6,9,11]. The placental emissions enhance the inammatory
response in PE [39] and even more in HELLP [10].
Increasing the sFlt1 level in pregnant rats may induce PE [40].
Elevation of soluble endoglin (sEng) in the blood of rats primed
with sFlt1 induced a syndrome similar to human HELLP [35].
Semiquantitation in blood from women with HELLP showed higher
soluble endoglin (sEng) values in HELLP than in PE [35]. A clinical
study reported higher sEng preterm levels in 2 women with HELLP
than in 34 women with PE [34]. A recent study reported similar

Table 2
Biomarkers in maternal blood predicting early onset HELLP or PE.

Biomarker Gestation weeks HELLP PE Ref. no. Function of marker

PP 13 814 # # [29] Development of fetal/maternal interface, immune regulation

2437 " " [28]

PlGF 814 # # [29,32] Angiogenic, prevents hypertension

Term ## # [33]

VEGF 1421 n.e. # [30] Angiogenic, prevents hypertension

32 " "" [31]

sFlt1 1017 n.e. " [32] Inhibits VEGF and PlGF. Anti-angiogenic
2540 "" " [33,35]

sEndoglin 1017 n.e. " [32] Inhibits TNF-b, inhibits vasodilation. Anti-angiogenic
Preterm "" " [34]a, [35]b
Term " " [36]

PP 13, placental protein 13; PlGF, placental growth factor; sFlt1, sVEGFR-1; n.e., not examined; ", higher than in pregnant controls (p < 0.05); "", higher than " (p < 0.05); a,
Levels in two women with HELLP higher than in 32 women with PE; b, Semiquantitative data.
120 U. Abildgaard, K. Heimdal / European Journal of Obstetrics & Gynecology and Reproductive Biology 166 (2013) 117123
values of sEng in PE and HELLP at term [36]. Different sEng levels at
preterm [34,35] might have a bearing on a possibly specic
pathogenetic role of sEng in HELLP, but additional preterm data are
needed. The placental emissions may particularly in HELLP induce
release of inammatory cytokines in the maternal circulation [10].
5.2. Differences between mRNA levels in HELLP and PE
In blood from symptomatic women the concentrations of fetal
mRNA coding for Flt1 (VEGFR-1) and Eng were several-fold higher
in HELLP than in early onset PE, both in plasma and cell fractions
[41]. In samples from gestation weeks 15 to 20, the differences
between women who later developed HELLP or PE and normal
controls were also marked, and distinct in the cell-free fractions
[42]. In cell-free fractions, the mRNA levels coding for Flt1 and Eng
were the best predictors for PE [43]. A score system based on mRNA
levels of 7 genes predicted the combined HELLPPE group with
high sensitivity (88.7%) at a specicity of 90%. The HELLP subgroup
had the highest mean score of 93.7, severe PE 79.3, and mild PE
56.3, as compared to a score of 9.4 in pregnant controls. Values in
severe PE and HELLP overlapped [42]. The statistically signicant
difference in mean scores suggests a more profound pathophysio-
logical deviation in HELLP than in PE.
5.3. Increased sHLA-DR in HELLP
Soluble HLA-DR (sHLA-DR) levels in maternal blood increased
in the second and third trimester [43]. sHLA-DR levels were
markedly increased in HELLP, but decreased in PE compared to
controls [43]. Hig sHLA-DR in HELLP syndrome was interpreted as a
maternal immune reaction against circulating fetal cells which
express paternal antigens, but could also represent fetal-derived
sHLA-DR molecules. The biological signicance is unclear. Stein-
born interpreted the ndings as maternal rejection of the fetus
[43].
5.4. Gene expression and histopathology in placenta
A microarray proling study on placenta samples at delivery
revealed 54 genes differentially expressed in early onset HELLP and
350 genes in early onset PE [44]. The transcriptomes in the two
syndromes largely overlapped. The inammatory response was
more pronounced in HELLP. Down-regulation was more frequent
in HELLP (239 genes) than in PE (67 genes) [44].
Histopathological comparisons of term placentas have shown a
lower frequency of intravillous thrombosis and villous infarcts in
HELLP than in PE [45] or no difference [25]. Apoptotic and
proliferation marker levels were higher in placenta from HELLP
than in PE [46]. Decidual dendritic cells stained differently and
reacted differently with decidual natural killer (dNK) cells in HELLP
compared to PE [47]. The placental expression of Fas Ligand (FasL)
was higher [48], and the expression in villous trophoblast
increased in HELLP compared to healthy pregnancy and PE [49].
6. Pathogenetic mechanisms in the mother with HELLP
6.1. The inammatory response
The inammatory response of normal pregnancy is more
enhanced in HELLP than in PE [10]. Fulminant disseminated
intravascular coagulation (DIC) in HELLP may develop superacutely
[50], apparently matching the time course of the Shwartzman
reaction [10]. The inammatory response with activation of
coagulation and complement is caused by syncytiotrophoblast
particles (STBM) and other placental products which interact with
maternal immune cells and vascular endothelial cells (EC) [51,52].
The concentrations in maternal blood of CRP, interleukin 6 [53]
and TNF-a [54] are more increased in HELLP than in PE. In 91
patients with HELLP and 86 patients with severe PE, white cells
counts were higher in HELLP and correlated with the severity of the
syndrome [55]. Complement is activated in HELLP [56]. Defective
regulation of complement may contribute to the development of
thrombotic microangiopathy and HELLP [57].
Strongly activated vascular ECs release active multimeric von
Willebrand factor (VWF) which promotes platelet aggregation and
may cause adherence of platelets to vessel intima. Active VWF
levels were higher in HELLP than in PE [58].
6.2. Thrombotic microangiopathy
Biopsies and autopsies in patients with HELLP have shown
thrombotic microangiopathy [23,59], which is an important
pathogenetic mechanism in HELLP. Infusion of TNFa in mice
caused microvascular thrombosis [60]. Damage to the vascular EC
by anti-angiogenic substances and exposure to TNFa combined
with high levels of active VWF in HELLP may interact and cause
thrombotic microangiopathy. Active VWF, the newly released,
multimeric form of VWF, is depolymerized in the circulation by the
metalloproteinase ADAMT13 which is decreased in HELLP [61]
probably contributing to the high levels of active VWF. Hulstein
et al. concluded that active vWF appears to contribute to
thrombocytopenia and thrombotic microangiopathy typical for
HELLP [58]. In a woman with anti-phospholipid syndrome (APLS)
and HELLP, extensive microangiopathy and multiorgan failure
developed, and the condition was termed catastrophic APLS [23].
6.3. Microangiopathic hemolytic anemia
Red blood cells are fragmented as they pass through vessels
with damaged endothelium and brin strands, resulting in
microangiopathic hemolytic anemia (MAHA). An abnormal blood
smear with schizocytes and/or burr cells may be a transient sign
[2]. The hemolysis may cause anemia and increase lactate
dehydrogenase (LDH) [2]. Free hemoglobin binds to unconjugated
bilirubin in the spleen, or to haptoglobin in blood plasma. Low
serum haptoglobin is characteristic in HELLP [3]. Products of the
intravascular hemolysis may activate coagulation and increase the
risk of DIC.
6.4. Liver and kidney dysfunctions
The hepatocyte injury is caused by placenta-derived FasL
(CD95L) which is toxic to human hepatocytes [48]. The content of
FasL in villous trophoblast is higher in HELLP than in PE [49], and
FasL concentration in maternal blood is elevated in HELLP [48].
FasL triggers the production of TNFa which may induce hepatocyte
apoptosis and necrosis. Staining with TNFa and elastase antibodies
in the liver was intense in HELLP [62]. Autopsies have shown
hepatocyte necrosis without fatty cell transformation, surrounded
by brin strands and hemorrhages, more rarely subcapsular
bleeding and infarcts [63]. Fibrin and leukostasis were seen in
sinusoids [23] probably as manifestations of thrombotic micro-
angiopathy. Hepatocyte damage in HELLP is enhanced by the
microangiopathy which impedes portal blood ow. Doppler
sonography in severe PE showed signicant reduction of portal
blood ow and total hepatic blood ow in 9 women with severe
preeclampsia who developed HELLP syndrome, but in none of the
49 women with severe PE alone [64].
Kidney dysfunction is usually moderate in HELLP and probably
caused by the glomerular endotheliosis of PE [8]. In a woman with
HELLP and post partum renal failure, renal biopsy revealed
thrombotic microangiopathy and acute tubular necrosis [59].
 U. Abildgaard, K. Heimdal / European Journal of Obstetrics & Gynecology and Reproductive Biology 166 (2013) 117123 121

6.5. Disseminated intravascular coagulation
Tissue factor (TF) is the main activator of coagulation. Fetal
microparticles exert TF activity [52]. Injured vascular EC may
expose TF on the surface. Activated platelets and high levels of
coagulation factors enhance activation which is promoted by the
thrombotic microangiopathy. Activated factors are inactivated by
the coagulation inhibitors. In a group of patients with severe HELLP
and MOF treated in an intensive care ward the concentrations of
thrombin-inhibitor complexes were high, indicating intense
activation of coagulation [65]. In patients with continued
activation the inhibitors may be exhausted. Fibrin and platelet
aggregates appear in the microcirculation, platelets and inhibitors
are consumed, and overt or uncompensated DIC is present [66].
HELLP may coexist with placental abruption, in which blood clots
and thrombin enter the maternal circulation and cause systemic
debrination.
In compensated DIC consumption is moderate, overt bleeding is
rare and the condition hardly affects the prognosis [66]. Increased
activation may be only partly compensated and may be associated
with thrombotic microangiopathy. The clinical condition may
rapidly progress to overt DIC, with bleeding from the skin and
mucous membranes and often intractable multiorgan failure
(MOF).
The informative laboratory tests regarding the diagnosis of DIC
in general are the platelet count, D-dimer, antithrombin and
protein C, thrombinantithrombin complex (TAT) and prothrom-
bin time [66]. Criteria for overt (uncompensated) DIC require
several abnormal ndings in these parameters [66]. In 128
consecutively admitted patients with HELLP and PE and 128
patients with PE only, overt DIC was rare and diagnosed in only 3
patients with HELLP and PE, and in 1 patient with PE [8]. In the
group of HELLP patients with DIC and MOF treated in an intensive
care ward the median antithrombin level was 60%, range 2072%.
Median TAT level was 50 mg/L, range 11931, compared to median
2.6 and range (1.714.8) in healthy controls [65].
Regarding the diagnosis of compensated DIC, D-dimer is
elevated in nearly all HELLP patients and in the majority of
patients with severe PE. Moderately elevated D-dimer is an
unspecic indicator of disease activity. In HELLP patients, the
angiopathy and the liver affection may result in decreased values
of platelet count, antithrombin and protein C. In a clinical study,
compensated DIC was diagnosed in all 15 consecutively admitted
HELLP patients, with mean values of antithrombin 66% and protein
C of 57% [67]. Similar results were found in other studies. Low
levels of antithrombin and protein C in such studies may reect the
combined effect of liver dysfunction, extravasation of blood
plasma, and irreversible binding to activated coagulation factors
in the DIC process. With high D-dimer levels, compensated DIC
may well be present.
Better insight into the complex pathophysiology of HELLP
patients may lead to improved clinical management [3]. The only
one of the conventional laboratory tests that may specically
reect the DIC process is the TAT assay. A value above 10 mg/L
suggests presence of DIC. Regrettably, data on TAT in HELLP and
DIC patients are mostly missing. We suggest that the TAT assay
may be added to platelet count, D-dimer and antithrombin (or
protein C) assays for monitoring HELLP patients.
6.6. Pathogenetic cascades
The pathogenesis of the maternal HELLP and PE syndromes may
be perceived as cascades of reactions, as shown in Fig. 1. The
suggested mechanisms shown in the gure and briey described in
the text of this review are based on statistically signicant data.
Some results obtained in single studies may be of limited validity
and a need for further studies is evident. Although the relative
importance of the substances inducing the thrombotic microangio-
pathy are not well known, the central role of the angiopathy in the
development of the clinical HELLP seems well established. It is not
only the main cause of the platelet consumption and the
microangiopathic anemia, but also contributes to the liver damage.
It is logical to assume that therapeutic inhibition of platelet
activation, and of anticoagulation could reduce the extent of
thrombotic microangiopathy. Clinical multicenter studies regarding
the possible prophylactic effect of anti-platelet or anticoagulation
medication in pregnant women with a high risk of HELLP seem
warranted. Pregnant women with a previous HELLP pregnancy

Cytokines, NKB sFlt1 sEng Cytokines TNF sEng FasL

Acvate EC:
Inam.response
EC Hypercoagulaon Acvate Platelets,
dysfuncon Acvated complement Leukocytes

Acve WVF TNF

Glomerular Arterial Thromboc Liver

endotheliosis hypertension
MAHA
microangiopathy damage

Preeclampsia HELLP

Fig. 1. Development of the maternal HELLP and preeclampsia syndromes. Bioactive substances emitted from placenta are shown in the top row of boxes (names of the
substances in italics). The substances are emitted from the oxidatively stressed placenta to the maternal blood. Their concentrations gradually increase and they in the second
half of pregnancy activate cascades of reactions terminating in the maternal signs and symptoms of HELLP syndrome (right side of panel) or preeclampsia (left side of panel).
The scheme is focused on pathways in the HELLP syndrome. For details regarding HELLP see text in Section 6. For details regarding preeclampsia see Ref. [8]. Reactants shown
in the HELLP pathways are also present at lower concentrations in preeclampsia. Abbreviations. HELLP, hemolytic anemia, elevated liver enzymes, low platelet count; NKB,
neurokinin B; sFlt1, soluble fms-like tyrosine kinase; sEng, soluble endoglin; Fas L, FasLligand, also called CD95 ligand; EC, vascular endothelial cells; VWF, von Willebrand
Factor; TNAa, tumor necrosis factor a; MAHA, microangiopathic hemolytic anemia.
122 U. Abildgaard, K. Heimdal / European Journal of Obstetrics & Gynecology and Reproductive Biology 166 (2013) 117123
would constitute an obvious patient group that could be studied. A
sufciently large prophylactic study would need a validated
selective test panel for detecting women at high risk of HELLP
syndrome.
7. Conclusion
Inadequate immune tolerance resulting in damage to the
invading fetal trophoblast occurring early in the rst trimester is
probably the essential initial phenomenon in the pathogenesis of
HELLP and PE. Messenger RNA levels in maternal blood are
signicantly more abnormal in HELLP than in PE, suggesting that
the early trophoblast lesion is more extensive in HELLP. Gene
expression in placenta is more abnormal in HELLP. The concentra-
tions of anti-angiogenic factors in maternal blood are similar, but
probably not identical, in HELLP and PE. The inammatory
response is excessive in HELLP. A combination of activated
coagulation and complement, with high circulating levels of
sEndoglin, sFlt1, TNFa and active von Willebrand factor may cause
the thrombotic microangiopathy in HELLP. The liver damage is
probably caused by circulating FasL from placenta, enhanced by
the angiopathy. Compensated DIC is probably frequent in HELLP,
but uncompensated DIC is rare.
Conict of interest
None reported.
Acknowledgements
We thank Anne Cathrine Staff for constructive criticism and
helpful suggestions, Nandor Gabor Than for advice and for
disclosing data on PP 13 metabolism prior to their publication,
and Kjell Haram who contributed to the literature search and to the
text on the maternal syndrome.
References
[1] Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet
count: a severe consequence of hypertension in pregnancy. American Journal of
Obstetrics and Gynecology 1982;142:15967.
[2] Sibai BM. Diagnosis, controversies, and management of the syndrome of
hemolysis, elevated liver enzymes, and low platelet count. Obstetrics and
Gynecology 2004;103:9819.
[3] Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: clinical issues and
management. A review. BMC Pregnancy and Childbirth 2009;9(8). http://
dx.doi.org/10.1186/1471-2393-9-8.
[4] Martin Jr JN, Rinehart BK, May WL, agann EF, Terrone DA, Blake PG. The
spectrum of severe preeclampsia: comparative analysis by HELLP (hemolysis,
elevated liver enzyme levels, and low platelet count) syndrome classication.
American Journal of Obstetrics and Gynecology 1999;180:137384.
[5] Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Montquin JM. The
classication and diagnosis of the hypertensive disorders of pregnancy: state-
ment from the international society for the study of hypertension in pregnancy
(ISSHP). Hypertension in Pregnancy 2001;20:ixxiv.
[6] James JL, Whitley GS, Cartwright JE. Pre-eclampsia: tting together the pla-
cental, immune and cardiovascular pieces. Journal of Pathology 2010;221:
36378.
[7] Habli M, Eftekhari N, Wiebracht E, et al. Long-term maternal and subsequent
pregnancy outcomes 5 years after hemolysis, elevated liver enzymes, and low
platelets (HELLP) syndrome. American Journal of Obstetrics and Gynecology
2009;201:385.e1.e5.
[8] Visser W, Wallenburg HC. Temporising management of severe pre-eclampsia
with and without the HELP syndrome. British Journal of Obstetrics and
Gynaecology 1995;102:1117.
[9] Redman CW. Preeclampsia: a multistress disorder. La Revue de me`dicine
interne 2011;325:5414.
[10] Landi B, Tranquilli AL. HELLP syndrome and placental inammatory pathology.
Minerva Ginecologica 2008;60:38998.
[11] Young BC, Levine RJ, Karumanchi SA. Pathogenesis of preeclampsia. Annual
Review of Pathology 2010;5:17392.
[12] Lachmeijer AM, Arngrimsson R, Bastiaans EJ, et al. A genome-wide scan for
preeclampsia in the Netherlands. European Journal of Human Genetics
2001;10:75864.
[13] Hupuczi P, Rigo B, Sziller I, Szabo G, Szigeti Z, Papp Z. Follow-up analysis of
pregnancies complicated by HELLP syndrome. Fetal Diagnosis and Therapy
2006;21:51922.
[14] Cnattingius S, Reilly M, Pawitan Y, Lichtenstein P. Maternal and fetal genetic
factors account for most of familial aggregation of preeclampsia: a population-
based Swedish cohort study. American Journal of Medical Genetics Part A
2004;130A:36571.
[15] Sziller I, Hupuczi P, Normand N, Halmos A, Papp Z, Witkin SS. Fas (TNFRSF6)
gene polymorphism in pregnant women with hemolysis, elevated liver
enzymes, and low platelets and in their neonates. Obstetrics and Gynecology
2006;107:5827.
[16] Nagy B, Savli H, Molvarec A, et al. Vascular endothelial growth factor (VEGF)
polymorphisms in HELLP syndrome patients determined by quantitative real-
time PCR and melting curve analyses. Clinica Chimica Acta 2008;389:12631.
[17] Muetze S, Leeners B, Ortlepp JR, et al. Maternal factor V Leiden mutation is
associated with HELLP syndrome in Caucasian women. Acta Obstetricia et
Gynecologica Scandinavica 2008;87:63542.
[18] Bertalan R, Patocs A, Nagy B, et al. Overrepresentation of BclI polymorphism of
the glucocorticoid receptor gene in pregnant women with HELLP syndrome.
Clinica Chimica Acta 2009;405:14852.
[19] van Rijn BB, Franx A, Steegers EA, et al. Maternal TLR4 and NOD2 gene variants,
pro-inammatory phenotype and susceptibility to early-onset preeclampsia
and HELLP syndrome. PLoS ONE 2008;3:e1865.
[20] Ward K. Searching for genetic factors underlying pre-eclampsia: recent prog-
ress and persistent challenges. Minerva Ginecologica 2008;60:399419.
[21] Mutze S, Rudnik-Schoneborn S, Zerres K, Rath W. Genes and the preeclampsia
syndrome. Journal of Perinatal Medicine 2008;36:3858.
[22] Sep S, Smits L, Prins M, Peeters L. Prediction tests for recurrent hypertensive
disease in pregnancy, a systematic review. Hypertension in Pregnancy
2010;29:20630.
[23] Koenig M, Roy M, Baccot S, Cuilleron M, de Filippis JP, Cathebras P. Thrombotic
microangiopathy with liver, gut, and bone infarction (catastrophic antipho-
spholipid syndrome) associated with HELLP syndrome. Clinical Rheumatology
2005;24:1668.
[24] Audibert F, Friedman SA, Frangieh AY, Sibai BM. Clinical utility of strict
diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and
low platelets) syndrome. American Journal of Obstetrics and Gynecology
1996;175:4604.
[25] Smulian JC, Shen-Schwarz S, Scorza WE, Kinzler WL, Vintzileos AM. A clin-
icohistopathological comparison between HELLP syndrome and severe pre-
eclampsia. The Journal of MaternalFetal and Neonatal Medicine
2004;16:28793.
[26] Redman CWG, Sargent IL. Immunology of pre-eclampsia. American Journal of
Reproductive Immunology 2010;63:53443.
[27] Balogh A, Pozgay J, Matko J, et al. Placental protein 13(PP 13/galectin-13)
undergoes lipid raft-associated subcellular redistribution in the syncytiotro-
phoblast in preterm preeclampsia and HELLP syndrome. American Journal of
Obstetrics and Gynecology 2011;205:156.e1156.e14.
[28] Than NG, Abdul RO, Magenheim R, et al. Placental protein 13 (galectin-13) has
decreased placental expression but increased shedding and maternal serum
concentrations in patients presenting with preterm pre-eclampsia and HELLP
syndrome. Virchows Archiv 2008;453:387400.
[29] Wortelboer EJ, Koster MP, Cuckle HS, Stoutenbeek PH, Schielen PC, Visser GH.
First-trimester placental protein 13 and placental growth factor: markers for
identication of women destined to develop early-onset pre-eclampsia. Brit-
ish Journal of Obstetrics and Gynaecology 2010;117:13849.
[30] Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk
of preeclampsia. New England Journal of Medicine 2004;350:67283.
[31] Bussen S, Bussen D. Inuence of the vascular endothelial growth factor on the
development of severe pre-eclampsia or HELLP syndrome. Archives of Gyne-
cology and Obstetrics 2011;284:5517.
[32] Noori M, Donald AE, Angelakopoulolou A, Hingorani AD, Williams DJ. Pro-
spective studies of placental angiogenic factors and maternal vascular func-
tion before and after preeclampsia and gestational hypertension. Circulation
2010;122:47887.
[33] Young B, Levine RJ, Salahuddin S, et al. The use of angiogenic biomarkers to
differentiate non-HELLP related thrombocytopenia from HELLP syndrome.
MaternalFetal and Neonatal Medicine 2010;23:36670.
[34] Levine RJ, Lam C, Quian C, et al. Soluble endoglin and other circulating
angiogenic factors in preeclampsia. New England Journal of Medicine
2006;355:9921005.
[35] Venkatesha S, Toporsian M, Lam C, et al. Soluble endoglin contributes to the
pathogenesis of preeclampsia. Nature Medicine 2006;12:6429.
[36] Hertig A, Liere P. New markers in preeclampsia. Clinica Chimica Acta
2010;411:15915.
[37] Huppertz B. Placental origins of preeclampsia: challenging the current
hypothesis. Hypertension 2008;51:9705.
[38] Sammar M, Nisemblat S, Fleischfarb Z, et al. Placenta-bound and body uid PP-
13 and its mRNA in normal pregnancy compared to preeclampsia, HELLP and
preterm delivery. Placenta 2011;32(Suppl. 1):S306.
[39] Redman CW, Sacks GP, Sargent IL. Preeclampsia: an excessive maternal
inammatory response to pregnancy. American Journal of Obstetrics and
Gynecology 1999;180:499506.
[40] Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine
kinase (sFlt1) may contribute to endothelial dysfunction, hypertension, and
proteinuria in preeclampsia. Journal of Clinical Investigation 2003;111:64958.
 U. Abildgaard, K. Heimdal / European Journal of Obstetrics & Gynecology and Reproductive Biology 166 (2013) 117123
[41] Purwosunu Y, Sekizawa A, Yoshimura S, et al. Expression of angiogenesis-
related genes in the cellular component of the blood of preeclamptic women.
Reproduction Science 2009;16:85764.
[42] Purwosunu Y, Sekizawa A, Okazaki S, et al. Prediction of preeclampsia by
analysis of cell-free messenger RNA in maternal plasma. American Journal of
Obstetrics and Gynecology 2009;200:386.e1.e7.
[43] Steinborn A, Rebmann V, Scharf A, Sohn C, Grosse-Wilde H. Soluble HLA-DR
levels in the maternal circulation of normal and pathologic pregnancy. Amer-
ican Journal of Obstetrics and Gynecology 2003;188:4739.
[44] Varkonyi T, Nagy B, Fule T, et al. Microarray proling reveals that placental
transcriptomes of early-onset HELLP syndrome and preeclampsia are similar.
Placenta 2011;32(Suppl.):S219.
[45] Vinnars MT, Wijnaendts LC, Westgren M, Bolte AC, Papadogiannakis N, Nasiell
J. Severe preeclampsia with and without HELLP differ with regard to placental
pathology. Hypertension 2008;51:12959.
[46] Jeschke U, Schiessl B, Mylonas. et al. Expression of the proliferation marker Ki-
67 and of p53 tumor protein in trophoblastic tissue of preeclamptic, HELLP,
and intrauterine growth-restricted pregnancies. International Journal of Gy-
necological Pathology 2006;25:35460.
[47] Scholz C, Toth B, Santoso L, et al. Distribution and maturity of dendritic cells in
diseases of insufcient placentation. American Journal of Reproductive Im-
munology 2008;60:23845.
[48] Strand S, Strand D, Seufert R, et al. Placenta-derived CD95 ligand causes liver
damage in hemolysis, elevated liver enzymes, and low platelet count syn-
drome. Gastroenterology 2004;126:84958.
[49] Prusak IK, Zekic Tomas S, Roje D. Apoptosis proliferation and Fas ligand
expression in placental trophoblast from pregnancies complicated by HELLP
syndrome or preeclampsia. Acta Obstetricia et Gynecologica Scandinavica
2011;90:115763.
[50] Catanzarite VA, Seinberg SM, Mosley CA, Landers CF, Cousins LM, Schneider
JM. Severe preeclampsia with fulminant and extreme elevation of aspartate
aminotransferase and lactate dehydrogenase levels: high risk for maternal
death. American Journal of Perinatology 1995;12:3103.
[51] van der Post JAM, Lok CAR, Boer K, Sturk A, Sargent IL, Nieuwland R. The
function of microparticles in pre-eclampsia. Seminars in Thrombosis and
Hemostasis 2011;37:14652.
[52] Gardiner C, Tannetta DS, Simms CA, Harrison P, Redman CW, Sargent IL.
Syncytiotrophoblast microvesicles released from pre-eclamptic placentae
exhibit increased tissue factor activity. Reference to distinctive histopatho-
logical alterations. PLoS ONE 2011;6:e26313.
[53] van Runnard Heimel PJ, Kavelaars A, Heijnen CJ, et al. HELLP syndrome is
associated with an increased inammatory response, which may be inhibited
by administration of prednisolone. Hypertension in Pregnancy 2008;27:
25365.
[54] Visser W, Beckmann I, Bremer HA, et al. Bioactive tumour necrosis factor alpha
in pre-eclamptic patients with and without the HELLP syndrome. British
Journal of Obstetrics and Gynaecology 1994;101:10812.
123
[55] Terrone DA, Rinehart BK, May WL, Moore A, Magann EF, Martin Jr JN. Leuko-
cytosis is proportional to HELLP syndrome severity: evidence for an inam-
matory form of preeclampsia. Southern Medical Journal 2000;93:76871.
[56] Haeger M, Unander M, Norder Hansen B, Tylman M, Bengtsson A. Comple-
ment, neutrophil and macrophage activation in women with severe pre-
eclampsia and the syndrome of hemolysis, elevated liver enzymes, and low
platelet count. Obstetrics and Gynecology 1992;79:1926.
[57] Fang CJ, Richards A, Liszewski MK, Kavanagh D, Atkinson JP. Advances in the
understanding of aHUS and HELLP. British Journal of Haematology
2008;143:33648.
[58] Hulstein JJ, van Runnard Heimel PJ, Franx A, et al. Acute activation of the
endothelium results in increased levels of active von Willebrand factor in
hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome.
Journal of Thrombosis and Hemostasis 2006;4:256975.
[59] Abraham KA, Kennelly M, Dorman AM, Walshe JJ. Pathogenesis of acute renal
failure associated with the HELLP syndrome: a case report and review of the
literature. European Journal of Obstetrics Gynecology and Reproductive Biol-
ogy 2003;108:99102.
[60] Yoshida H, Yilmaz CE, Granger DN. Role of tumor necrosis factor-alpha in the
extraintestinal thrombosis associated with colonic inammation. Inamma-
tory Bowel Diseases 2011;17:221723.
[61] Lattuada A, Rossi E, Calzarossa C, Candol R, Mannucci PM. Mild to moderate
reduction of a von Willebrand factor cleaving protease (ADAMTS-13) in
pregnant women with HELLP microangiopathic syndrome. Haematologica
2003;88:102934.
[62] Halim A, Kanyama N, El Maradny E, et al. Immunohistological study in cases of
HELLP syndrome (hemolysis, elevated liver enzymes and low platelets) and
acute fatty liver of pregnancy. Gynecologic and Obstetric Investigation
1996;41:10612.
[63] Tsokos M, Longauer F, Kardosova V, Gavel A, Anders S, Schulz F. Maternal death
in pregnancy from HELLP syndrome. A report of three medico-legal autopsy
cases with special reference to distinctive histopathological alterations. In-
ternational Journal of Legal Medicine 2002;116:503.
[64] Kawabata I, Nakai A, Takeshita T. Prediction of HELLP syndrome with assess-
ment of maternal dual hepatic blood supply by using Doppler ultrasound.
Archives of Gynecology and Obstetrics 2006;274:3039.
[65] Andersson TR, Sandset PM, Nustad K, Abildgaard U. Evidence that heparin
cofactor II participates in the control of disseminated intravascular
coagulation. In: Mu ller-Berghaus, et al., editors. DIC: pathogenesis, diagnosis
and therapy of disseminated intravascular brin formation. Amsterdam:
Elsevier; 1993. p. 1258.
[66] Taylor Jr FB, Toh CH, Hoots WK, Wada H, Levi M. Towards denition, clinical
and laboratory criteria, and a scoring system for disseminated intravascular
coagulation. Thrombosis and Haemostasis 2001;86:132730.
[67] de Boer K, Buller HR, ten Cate JW, Treffers PE. Coagulation studies in the
syndrome of haemolysis, elevated liver enzymes and low platelets. British
Journal of Obstetrics and Gynaecology 1991;98:427.